This specification discloses, inter alia, drug compounds that inhibit cell proliferation, antibody-drug conjugates made therefrom, drug-linker compounds for making such conjugates, uses of such compounds and their antibody-drug conjugates, and methods and intermediates for their making.
Double helical DNA has two longitudinal spiral grooves running along its exterior, much like the stripes on a barbershop pole. The two grooves are not identical: one, called the major groove, is much wider than the other, called the minor groove.
The width of the minor groove is approximately equal to the thickness of a benzene ring. Many biologically active DNA-binding molecules—whether synthetic or naturally occurring—are substantially planar polyaromatic molecules having an arcuate footprint, such shape enabling them to fit snugly into the minor groove. For short, a DNA minor groove binding molecule is referred to herein as an MGB, or minor groove binder.
One type of MGB is a dimer of two polyaromatic units, each comprising a benzodiazepine and a tetrahydroisoquinoline (“THIQ”) ring system, as shown by the representative structure below. Such MGBs are disclosed in Zhang et al. 2016, McDonald et al. 2016, and Junutula et al. 2016.

Another type of MGB is also a dimer of two polyaromatic units, but in this instance comprising a pyrrolobenzodiazepine (“PBD”) ring system, as illustrated by the structure below. Bose et al. 1992 and Thurston et al. 1993 are exemplary publications disclosing such MGBs.

Yet another type of MGB is represented by the natural products distamycin and netropsin, comprising aminopyrrolecarboxylic acid moieties linked by amide bonds:

Still yet another type of MGB is represented by the natural products duocarmycin SA and yatakemycin, which have a characteristic cyclopropapyrroloindole (“CPI”) subunit and are therefore often referred to as CPI compounds. Members in this class include their seco (ring-opened) counterparts.

There exist a number of disclosures of synthetic compounds combining structural features from different types of MGBs. Rahman et al. 2013 disclose compounds combining a PBD moiety and a distamycin-like moiety, such as:

Zhang et al. 2016 and Junutula et al. 2016 disclose MGB heterodimers comprising one THIQ containing unit and one PBD unit. An illustrative structure is shown below.

Yet other disclosures of compounds combining different MGB moieties include: Ahmed et al. 2012; Baraldi et al. 1998 and 1999; Demayanthi et al. 1999; Kumar and Lown 2002 and 2003; Kumar et al. 2002 and 2005; Reddy et al. 2000; Tercel et al. 2003; Thurston et al. 2016; and Wells et al. 2006.
The biological activity of MGBs derives from their ability to bind to DNA and disrupt its transcription and, in some instances, chemically react with DNA and damage it. Consequently, many MGBs are highly cytotoxic. There is interest in the use of MGBs for the treatment of cancer, as their cytotoxicity can make them effective in killing cancer cells.
A type of anticancer agent that is generating strong interest is a conjugate, in which a drug is attached to a targeting agent that binds to a ligand on the cancer cell. The targeting agent, by binding to its ligand, directs the drug to the cancer cell, where it is released by one of several mechanisms, to act on the cancer cell.
A common type of conjugate is an antibody-drug conjugate (“ADC,” also referred to as an immunoconjugate). In an ADC, a drug (synonymously therapeutic agent, cytotoxin, payload, or warhead) is covalently linked to an antibody whose antigen is a tumor associated antigen—i.e., an antigen expressed by a cancer cell. MGBs have potential as the drug in an ADC.
The moiety covalently linking the antibody and the drug is referred to as the linker. Where each antibody has one drug attached to it, the structure of an ADC can be represented generically as:[Antibody]−[Linker]−[Drug]
The antibody, upon binding to its antigen, delivers the ADC to the cancer site. There, cleavage of the linker or degradation of the antibody releases the drug. Frequently, the ADC is internalized by endocytosis into the target cell and release of the drug takes place inside it. While the ADC is circulating in the blood, the drug is held inactive because of its linkage to the antibody. Consequently, the drug in an ADC can be much more potent (cytotoxic) than an ordinary chemotherapy agent because its localized release reduces systemic toxicity. For a review on ADCs, see Schrama et al. 2006.
Full citations for the documents cited herein by first author or inventor and year are listed at the end of this specification.